Correction: The importance of investing in data, models, experiments, team science, and public trust to help policymakers prepare for the next pandemic.

[This corrects the article DOI: 10.1371/journal.pgph.0002601.].

Exploring the Big Data Paradox for various estimands using vaccination data from the global COVID-19 Trends and Impact Survey (CTIS).

Selection bias poses a substantial challenge to valid statistical inference in nonprobability samples. This study compared estimates of the first-dose COVID-19 vaccination rates among Indian adults in 2021 from a large nonprobability sample, the COVID-19 Trends and Impact Survey (CTIS), and a small probability survey, the Center for Voting Options and Trends in Election Research (CVoter), against national benchmark data from the COVID Vaccine Intelligence Network. Notably, CTIS exhibits a larger estimation error on average (0.37) compared to CVoter (0.14). Additionally, we explored the accuracy (regarding mean squared error) of CTIS in estimating successive differences (over time) and subgroup differences (for females versus males) in mean vaccine uptakes. Compared to the overall vaccination rates, targeting these alternative estimands comparing differences or relative differences in two means increased the effective sample size. These results suggest that the Big Data Paradox can manifest in countries beyond the United States and may not apply equally to every estimand of interest.

Rescue Blood Contamination in scRNA-Seq Data by Originator, a Computational Deciphering Tool using Genetic and Contextual Information.

Single-cell RNA sequencing (scRNA-Seq) data from complex human tissues have prevalent blood cell contamination due to the sample preparation process and may comprise cells of different genetic makeups. To reveal such complexity and annotate cells appropriately, we propose the first-of-its-kind computational framework, Originator, which deciphers single cells by genetic origin and separates blood cells from tissue-resident cells. We show that blood contamination is widely spread in scRNA-Seq data from a variety of tissues. We warn of the significant biases in downstream analysis without considering blood contamination and genetic contexts using pancreatic ductal adenocarcinoma and placenta data, respectively.

The importance of investing in data, models, experiments, team science, and public trust to help policymakers prepare for the next pandemic.

The COVID-19 pandemic has brought about valuable insights regarding models, data, and experiments. In this narrative review, we summarised the existing literature on these three themes, exploring the challenges of providing forecasts, the requirement for real-time linkage of health-related datasets, and the role of 'experimentation' in evaluating interventions. This literature review encourages us to broaden our perspective for the future, acknowledging the significance of investing in models, data, and experimentation, but also to invest in areas that are conceptually more abstract: the value of 'team science', the need for public trust in science, and in establishing processes for using science in policy. Policy-makers rely on model forecasts early in a pandemic when there is little data, and it is vital to communicate the assumptions, limitations, and uncertainties (theme 1). Linked routine data can provide critical information, for example, in establishing risk factors for adverse outcomes but are often not available quickly enough to make a real-time impact. The interoperability of data resources internationally is required to facilitate sharing across jurisdictions (theme 2). Randomised controlled trials (RCTs) provided timely evidence on the efficacy and safety of vaccinations and pharmaceuticals but were largely conducted in higher income countries, restricting generalisability to low- and middle-income countries (LMIC). Trials for non-pharmaceutical interventions (NPIs) were almost non-existent which was a missed opportunity (theme 3). Building on these themes from the narrative review, we underscore the importance of three other areas that need investment for effective evidence-driven policy-making. The COVID-19 response relied on strong multidisciplinary research infrastructures, but funders and academic institutions need to do more to incentivise team science (4). To enhance public trust in the use of scientific evidence for policy, researchers and policy-makers must work together to clearly communicate uncertainties in current evidence and any need to change policy as evidence evolves (5). Timely policy decisions require an established two-way process between scientists and policy makers to make the best use of evidence (6). For effective preparedness against future pandemics, it is essential to establish models, data, and experiments as fundamental pillars, complemented by efforts in planning and investment towards team science, public trust, and evidence-based policy-making across international communities. The paper concludes with a 'call to actions' for both policy-makers and researchers.

Survival impact of increasing time to IMRT initiation following induction chemotherapy in nasopharyngeal carcinoma: A propensity score-matched analysis.

PURPOSE: To explore the prognostic impact of waiting time for radiotherapy (RT) after induction chemotherapy (IC) for nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: A total of 648 NPC patients receiving IC between 2009 and 2011 were included. Propensity score matching (PSM) was performed to balance the variables. Survival outcomes were compared in subgroups based on time to RT (TTR) after IC. RESULTS: The optimal cutoff point for TTR was 28 days. A total of 330 patients were selected by 1:2 PSM. Stratified and dichotomized TTRs were both strongly correlated with prognosis. Patients with TTR > 28 days had significantly worse 5-year LRFS, DMFS, DFS and OS than those with TTR ≤ 28 days (P < 0.05). In multivariate analysis, TTR > 28 days was an independent predictor of worse LRFS [HR=2.08; 95% CI, 1.18-3.66; P = 0.011), DMFS (HR=1.65; 95% CI, 1.04-2.62; P = 0.033), DFS (HR=1.86; 95% CI, 1.35-2.62; P < 0.001) and OS (HR=1.90; 95% CI, 1.26-2.85; P < 0.001). High-risk patients with T4 or N2-3 disease were highly susceptible to RT delay with impaired DFS and OS. In high-risk patients with TTR > 28 days, concurrent chemotherapy yielded better DMFS (70.9% vs. 52.0%, P  =  0.041), DFS (52.5% vs. 34.3%, P = 0.039) and OS (70.3% vs. 53.2%, P = 0.048). CONCLUSIONS: Prolonged waiting is detrimental to survival in NPC, and it is strongly recommended to start RT within 28 days after IC. T4/N2-3 NPC has a higher risk of treatment failure with delayed RT. With potential protection against RT delay, concurrent chemotherapy should be performed in high-risk patients as salvage therapy.

The impact of body composition parameters on severe toxicities in patients with locoregionally advanced nasopharyngeal carcinoma undergoing neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NACT) treatment in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) can lead to considerable toxicity. Loss of skeletal muscle mass showed relevance with increased chemotherapy-related toxicity and poor survival in various cancer types, but its significance in NPC remains unclear. This study aimed to investigate the relationship between body composition parameters and the incidence of NACT toxicity in LA-NPC patients. METHODS: Ninety-six LA-NPC patients were retrospectively enrolled. All patients had pre-treatment abdominal computed tomography (CT) images to exclude distant metastasis. Lean body mass (LBM, kg) was estimated based on cross-sectional muscle area at the third lumbar vertebra (L3) level on CT, and skeletal muscle index (SMI, cm2/m2) was calculated. Doses of chemotherapeutics were normalized as dose/LBM (mg/kg). Grade 3-4 toxicity was defined as severe. The associations between body composition parameters and severe toxicities were assessed using univariate and multivariate logistic regression analyses. Optimal cutoff points were obtained with a receiver operating characteristic (ROC) curve. RESULTS: Of the 96 patients, 81.2% received the docetaxel + cisplatin (TP) regimen, and the rest received the gemcitabine + cisplatin (GP) regimen. Males had more LBM and a higher SMI at baseline, and females received a markedly higher dose of docetaxel and gemcitabine per kg LBM (P<0.001). With a cutoff value of 52.7 cm2/m2, patients with higher SMI showed lower risk of severe toxicity. For TP regimen group, those presented with grade 3-4 neutropenia had a higher dose per kg LBM. Univariate and multivariate analyses showed that the LBM-adjusted dose was significantly associated with severe neutropenia in the TP regimen group (P<0.001). The LBM-normalized docetaxel cutoff value of 2.64 mg/kg was a prominent predictor of ≥ grade 3 neutropenia (P=0.003), but a higher dose of docetaxel per kg LBM did not provide a better objective response rate. CONCLUSIONS: LA-NPC patients with lower SMI and higher dose of docetaxel per kg LBM are more likely to suffer from severe treatment-related toxicity. Higher docetaxel dose per kg LBM is a prominent predictor for severe neutropenia, but not for NACT response. LBM showed good potential in toxicity risk prediction and dose determination.

Effect of COVID-19 Epidemic on Delay of Diagnosis and Treatment Path for Patients with Nasopharyngeal Carcinoma.

INTRODUCTION: 2019 novel coronavirus disease (COVID-19) outbreaks have been occurring in China and other countries in the world. To prevent further spread of the disease, restrictions of population flow from the government and measures to reduce virus transmission from hospitals may lead to the delay of diagnosis and treatment in patients with nasopharyngeal carcinoma (NPC). METHODS: All NPC patients with radiotherapy indications were included from 20 weekdays before (group A) and after (group B) January 31, 2020, when the institute began to take measures against COVID-19. The waiting intervals of each step and variation from the diagnosis and treatment path of NPC between two groups were compared. RESULTS: Significant differences were found between the group A and group B in the median waiting days for pathological biopsy (5 vs 15, P=0.012), radiotherapy immobilization and simulation (3.5 vs 16.5, P<0.001), validation of position and plan (20 vs 61, P<0.001) and initiation of radiotherapy (28 vs 36, P=0.005). During the waiting period of radiotherapy, 32.4% of the NPC patients received an additional one cycle of chemotherapy to the original treatment strategy. CONCLUSION: The prevalence of COVID-19 caused delay in the diagnosis and treatment of NPC patients to a certain extent. Additional chemotherapy could be considered to counteract the effect of treatment delay. More specific measures should be taken to balance the risk of delayed diagnosis and treatment of NPC and infection of COVID-19.

Interplay of Tumor Spread, Volume and Epstein-Barr Virus DNA in Nasopharyngeal Carcinoma: Feasibility of An Integrative Risk Stratification Scheme.

Purpose: To investigate the inter-correlation of tumor spread, volume and quantitative plasma Epstein-Barr virus DNA level (pEBV DNA), and to further assess the prognostic efficacy of a novel risk stratification combining anatomic, volumetric and biological features in nasopharyngeal carcinoma (NPC). Methods and Materials: One hundred and twelve patients with non-metastatic NPC were prospectively enrolled. Correlation of pEBV DNA with tumor invasiveness, lymph node (LN) metastasis, tumor volume and classification was tested by univariate and multivariate analyses. 5-year distant metastasis free survival (DMFS) was evaluated using Kaplan-Meier method and Cox proportional hazards model. Results: Tumor volume, TNM stage and pEBV DNA were strongly inter-correlated to each other. Nodal volume, skull base invasion and LN metastasis to supraclavicular fossa were determined to be independent predictors for pEBV DNA level. To exclude collinearity, a risk stratification based on combination of EBV DNA, nodal volume and anatomic features was established, offering significant distinguishing ability in 5-year DMFS. Further multivariate Cox regression analysis found the novel stratification to be independent predictor of DMFS. Conclusions: Both anatomic spread and tumor volume contribute to pEBV DNA level, leading to strong inter-correlation between NPC stage, volume and EBV DNA. The proposed risk stratification combining anatomic, volumetric and biological features showed potential in refining DMFS prediction.

Quantitative Metastatic Lymph Node Regions on Magnetic Resonance Imaging Are Superior to AJCC N Classification for the Prognosis of Nasopharyngeal Carcinoma.

PURPOSE: Quantitative lymph node burden has been demonstrated to be a critical prognosticator in various malignancies, yet it was seldom explored in nasopharyngeal carcinoma (NPC). This study aimed to investigate the impact of the number of metastatic lymph node regions (LRN) on prognosis of NPC and to establish a new N classification system based on LRN. METHODS AND MATERIALS: The magnetic resonance images (MRI) of 354 nondisseminated NPC patients before radical treatment were retrospectively evaluated. The regions with positive lymph nodes (LNs) were quantified according to 2013 updated guidelines for neck node levels. Prognostic value of LRN on distant metastasis-free survival (DMFS) was analyzed using multivariable Cox model after adjusting for other nodal characteristics and therapeutic factors. RESULTS: LRN strongly correlated with the size, laterality, level, extracapsular extension (ECE), and necrosis of LNs. Risk of distant metastasis significantly escalated with increased LRN (P<0.001). 5-year DMFS for LRN 0-1, 2-6, and ⩾7 was 97.0%, 86.7%, and 69.7%, respectively. In multivariable Cox analysis, LRN (HR 2.45; 95% CI 1.55-3.88; P<0.001) and maximal LN diameter (MLD) >6cm (HR 4.11; 95% CI 2.23-7.56; P<0.001) were identified as independent predictors of DMFS. Laterality and level showed no prognostic significance when accounting for LRN. A novel N classification scheme was derived by recursive partitioning analysis based on LRN and MLD. Compared with the 7th and 8th edition of American Joint Committee on Cancer (AJCC) systems, the new stratification exhibited better accuracy in predicting survivals. CONCLUSIONS: LRN is a promising quantitative predictor of survival in NPC, eclipsing other classic LN characteristics in prognostic value. The simplified N classification scheme with LRN and MLD is predictive and practical, thus warranting further validation in future.

Treatment outcomes and late toxicities of 869 patients with nasopharyngeal carcinoma treated with definitive intensity modulated radiation therapy: new insight into the value of total dose of cisplatin and radiation boost.

This study was to report the long-term outcomes and toxicities of nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). From 2009 to 2010, 869 non-metastatic NPC patients treated with IMRT were retrospectively enrolled. With a median follow-up of 54.3 months, the 5-year estimated local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were 89.7%, 94.5%, 85.6%, 76.3%, 84.0%, respectively. In locally advanced NPC, gender, T, N, total dose of cisplatin more than 300 mg/m(2) and radiation boost were independent prognostic factors for DMFS and DFS. Age, T, N and total dose of cisplatin were independent prognostic factors for OS. Radiation boost was an adverse factor for LRFS, RRFS, DMFS and DFS. Concurrent chemotherapy was not an independent prognostic factor for survival, despite marginally significant for DMFS in univariate analysis. Concurrent chemotherapy increased xerostomia and trismus, while higher total dose of cisplatin increased xerostomia and otologic toxicities. In conclusion, IMRT provided satisfactory long-term outcome for NPC, with acceptable late toxicities. Total dose of cisplatin was a prognostic factor for distant metastasis and overall survival. The role of concurrent chemotherapy and radiation boost in the setting of IMRT warrants further investigation.